Throughout this application various publications are referred to by number in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
Breast cancer is one of the most frequent malignant neoplasms occurring in women in developed countries and metastasis of breast cancer is the main cause of death in these patients. The idea of personalized medicine and molecular profiling for prognostic tests has lead to a plethora of studies in the past 10 years in search of genetic determinants of metastasis. Such studies have identified gene sets, or “signatures”, the expression of which in primary tumors is associated with higher risk of metastasis and poor disease outcome for the patients. Early methods of analysis treated the tumor as a whole, without respect to the different metastatic stages or the microenvironments. For example, the first molecular classification of tumors and identification of gene signatures associated with metastasis, were all derived from whole pieces of tumor tissue (1-6). These signatures were predictive of metastasis in patients and an important step towards applying these methods in clinical care. However, these signatures, mostly built to act as a general prognostic tool for the clinic, gave little information about the molecular biology of the different cell types comprising the tumor tissue and little insight into the specific mechanisms of metastasis.
We now know that tumors are highly heterogeneous, that not all cells within a tumor are migratory and invasive, and that the tumor microenvironment gives spatial-temporal cues to tumor cells for invasion and metastasis. In addition, metastasis is a multi-step process that involves the escape of cells from the primary tumor either via lymphatic or blood vessels, transport to and arrest in a target organ, and growth of metastases in the target organ. Each of these steps is a multicomponent process, with potentially different tumor cell properties and molecules playing critical roles, and therefore each of these steps separately deserves detailed attention. More recent signatures give such emphasis in detailed analysis of the role of the microenvironment in metastasis (7), as well as analysis of the tissue tropism for metastatic growth (8). The latter studies have been informative in prognosis of site-specific metastasis, as well as the cell biology behind the mechanisms of extravasation, homing and colonization at the distant metastatic site (9-11). However, little information is available about the crucial early steps of the metastatic cascade: migration, invasion and entry of tumor cells into the systemic circulation.
The present invention addresses this need by providing a gene expression profile specific for invasion and dissemination in human tumors.